PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

Ross, Rachel; León, Silvia; Madara, Joseph C.; Schafer, Danielle; Fergani, Chrysanthi; Maguire, Caroline; Verstegen, Anne M.J.; Brengle, Emily; Kong, Dong; Herbison, Allan E.; Kaiser, Ursula B.; Lowell, Bradford B.; Navarro, Vı́ctor

doi:10.7554/elife.35960

Cited by 76 publications

(54 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Activation of leptin signaling in the PMV is sufficient to restore pubertal development and fertility in leptin-deficient mice (Donato et al 2011a,b), whereas specific lesions of the PMV caused alterations of Kiss1 neurons and delayed puberty (Donato et al 2013). The nature of these PVM neurons relying on leptin actions remains enigmatic, but recent reports suggest that they may include a set of PACAP neurons, which project to ARC and AVPV Kiss1 neurons and whose deletion caused delayed puberty and perturbed reproductive function in female mice (Ross et al 2018). In addition, other populations of leptin-responsive neurons outside the PVN, such as GABAergic or NO-producing neurons, the latter sited in the POA, have been shown to contribute in mediating the actions of leptin on puberty onset and the HPG axis, via modulation of Kiss1 neurons (Bellefontaine et al 2014, Martin et al 2014.…”

Section: Metabolic Control Of Puberty In Mammals: Key Hormonal and Nementioning

confidence: 99%

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Vázquez

Velasco

Tena‐Sempere

2019

Journal of Endocrinology

View full text Add to dashboard Cite

Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.

show abstract

Section: Metabolic Control Of Puberty In Mammals: Key Hormonal and Nementioning

confidence: 99%

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Vázquez

Velasco

Tena‐Sempere

2019

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…63,64 The PMV, which expresses glutamate and pituitary adenylate cyclase activating polypeptide and responds to leptin treatment with phosphorylation of signal transducer and activator of transcription 3 (STAT3), may communicate nutritional state information to GnRH neurons by modulating the activity of Kiss1 neurons. 65 Leptin signals via several pathways in hypothalamic neurons, including phosphorylation of STAT3 and phosphoinositide 3-kinase (PI3K). [65][66][67] Interestingly, mice containing a mutant leptin receptor (LRb) incapable of STAT3 signaling are obese but remain fertile.…”

Section: Role Of Kisspeptin Neurons In Feedingmentioning

confidence: 99%

“…65 Leptin signals via several pathways in hypothalamic neurons, including phosphorylation of STAT3 and phosphoinositide 3-kinase (PI3K). [65][66][67] Interestingly, mice containing a mutant leptin receptor (LRb) incapable of STAT3 signaling are obese but remain fertile. 67 This would indicate that leptin signaling via STAT3 is essential for maintaining normal body weight but not for maintaining normal fertility, which may be dependent on other signaling pathways including PI3K.…”

Section: Role Of Kisspeptin Neurons In Feedingmentioning

confidence: 99%

Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

2019

View full text Add to dashboard Cite

Hypothalamic control of fertility is the quintessential homeostatic function. However, fertility is metabolically demanding; so, there must be coordination between energy states and reproductive functions. Because gonadotropin-releasing hormone (GnRH) neurons are devoid of many of the critical metabolic hormone receptors for sensing nutrient levels, it has long been recognized that the sensing of energy stores had to be done by neurons presynaptic to GnRH neurons. Some of the obvious players have been the anorexigenic proopiomelanocortin (POMC) and orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, both of which are in close apposition to the median eminence, a circumventricular organ. Indeed, POMC and NPY/AgRP neurons are inversely regulated by glucose and metabolic hormones including insulin and leptin. However, their synaptic connections with GnRH neurons are sparse and/or GnRH neurons are lacking the postsynaptic receptors to mediate the appropriate physiological response. Kisspeptin neurons were discovered in the early part of this century and subsequently shown to project to and control GnRH neuronal excitability. In fact, more recently the arcuate kisspeptin neurons have been identified as the command neurons driving pulsatile release of GnRH. Subsequently, it was shown that arcuate kisspeptin neurons express not only steroid hormone receptors but also metabolic hormone receptors such that similar to POMC neurons, they are excited by insulin and leptin. Therefore, based on the premise that arcuate kisspeptin neurons are the key neurons coordinating energy states with reproduction, we will review not only how these vital neurons control pulsatile GnRH release but how they control energy homeostasis through their synaptic connections with POMC and NPY/AgRP neurons and ultimately how E2 can regulate their excitability.

show abstract

“…This can be due to disturbed mechanisms of this complex process at several levels. For example, PACAP affects hormonal regulation that may affect fertility . At the gonadal levels, PACAP affects both spermato‐ and folliculogenesis .…”

Section: Discussionmentioning

confidence: 99%

Phenotypic characterization of testicular immune cells expressing immune checkpoint molecules in wild‐type and pituitary adenylate cyclase‐activating polypeptide‐deficient mice

Meggyes

Lajko

Fülöp

et al. 2019

American J Rep Immunol

View full text Add to dashboard Cite

Problem Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a neuropeptide having several regulatory functions in the nervous system and in peripheral organs including those of the reproductive system. PACAP‐deficient male mice have several morphological, biochemical, behavioral defects and show disturbed signaling in spermatogenesis affecting fertility in PACAP KO mice. Reproductive functions such as fertility, mating, and maternal behaviors have been widely investigated, but no immune analyses are available regarding the testicular immune‐privileged environment in male PACAP‐deficient mice. Method of Study We performed detailed immunophenotyping of testicular immune cells and investigated the expression of TIM‐3 and PD‐1 Immune checkpoint molecules of immune cells together with the detection of galectin‐9 and perforin. We investigated the percentage of numerous immune cell populations in the testis of wild‐type and PACAP‐deficient mice. Results We demonstrated a significant increase in the frequency of testicular CD8+ T cells together with the decrease in Treg cell number obtained from PACAP KO mice compared with wild‐type mice. Investigating Immune checkpoint receptors, only PD‐1 showed a significantly decreased expression in CD8+ T cells in PACAP KO mice compared with wild‐type suggesting an impaired PD‐1/PD‐L1 pathway. Regarding TIM‐3 expression, we did not find any significant difference between the investigated groups. Conclusion We hypothesize that these local changes may result in an immune activation with disturbed testicular immunoregulation in PACAP KO mice; however, determining the exact function requires further investigations. Our data further support the view that besides a systemic immune tolerance, localized active immunosuppression is involved in the regulation of testicular immune privilege.

show abstract

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

Cited by 76 publications

References 48 publications

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

Phenotypic characterization of testicular immune cells expressing immune checkpoint molecules in wild‐type and pituitary adenylate cyclase‐activating polypeptide‐deficient mice

Contact Info

Product

Resources

About